Exploring the Ubiquinone Binding Cavity of Respiratory Complex I

Proton pumping respiratory complex I is a major player in mitochondrial energy conversion. Yet little is known about the molecular mechanism of this large membrane protein complex. Understanding the details of ubiquinone reduction will be prerequisite for elucidating this mechanism. Based on a recen...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-10, Vol.282 (40), p.29514-29520
Main Authors: Tocilescu, Maja A., Fendel, Uta, Zwicker, Klaus, Kerscher, Stefan, Brandt, Ulrich
Format: Article
Language:English
Subjects:
Catalysis
Electron Spin Resonance Spectroscopy
Electron Transport Complex I - chemistry
Iron-Sulfur Proteins - chemistry
Models, Molecular
Molecular Conformation
Mutagenesis, Site-Directed
Mutation
Point Mutation
Protein Binding
Protons
Thermus thermophilus - metabolism
Threonine - chemistry
Ubiquinone - chemistry
Yarrowia - metabolism
Yarrowia lipolytica
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Summary:Proton pumping respiratory complex I is a major player in mitochondrial energy conversion. Yet little is known about the molecular mechanism of this large membrane protein complex. Understanding the details of ubiquinone reduction will be prerequisite for elucidating this mechanism. Based on a recently published partial structure of the bacterial enzyme, we scanned the proposed ubiquinone binding cavity of complex I by site-directed mutagenesis in the strictly aerobic yeast Yarrowia lipolytica. The observed changes in catalytic activity and inhibitor sensitivity followed a consistent pattern and allowed us to define three functionally important regions near the ubiquinone-reducing iron-sulfur cluster N2. We identified a likely entry path for the substrate ubiquinone and defined a region involved in inhibitor binding within the cavity. Finally, we were able to highlight a functionally critical structural motif in the active site that consisted of Tyr-144 in the 49-kDa subunit, surrounded by three conserved hydrophobic residues.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M704519200